Familial amyloid polyneuropathy (FAP) is a neurodegenerative disorder characterized by the extracellular deposition of amyloid fibrils composed of mutant forms of transthyretin (TTR) in several tissues, particularly the peripheral nervous system. Among the point mutations in TTR promoting amyloidogenesis, the most common is a substitution of Val for Met at position 30 (V30M). TTR amyloid deposits are distributed diffusely in the peripheral nervous system, involving nerve trunks, plexuses, and sensory and autonomic ganglia. Amyloid deposits in peripheral nerves occur especially in the endoneurium, where they appear close to Schwann cells (SCs) and collagen fibrils. In severely affected nerves, endoneurial contents are replaced by amyloid, and few nerve fibers retain viability. By contrast, the CNS in FAP is relatively spared, except for the ependymal lining and leptomeninges. Outside the nervous system, extensive amyloid deposits have been observed throughout connective tissue in a perivascular distribution.
The accumulation of extracellular, crossed β-sheet fibrils is a hallmark of amyloidoses. Pathologically, fibrillar accumulation appears to be closely linked to dysfunction of the surrounding cells and vasculature. This view of FAP pathogenesis would suggest that nerve fiber degeneration results from multifocal compression by amyloid deposits. However, unmyelinated fibers (UFs) that are primarily affected in FAP are more resistant to compression than myelinated fibers (MFs). Similarly, despite the presence of vascular amyloid, evidence of compromised blood flow sufficient to adversely affect organ function has not been demonstrated in FAP.
Local cellular activation, ultimately resulting in cell dysfunction and death, may contribute to the pathogenesis of amyloid-related disorders. In Alzheimer's disease (AD), the close association between expression of inflammatory mediators (cytokines, chemokines, complement proteins, acute phase reactants), activated astrocytes and microglia, and neuritic plaques has suggested a prominent role for immune/inflammatory pathways in the neurodegenerative process. Among the candidate mechanisms through which pathogenic forms of amyloidogenic molecules might perturb cellular properties is engagement of cellular receptors. The receptor for advanced glycation end products (RAGE) displays increased expression in FAP tissues and has been shown to bind fibrillar TTR triggering nuclear factor (NF)-κB expression.
The possible involvement of RAGE in the biology of amyloidoses was strengthened by the recent demonstration that RAGE bound amyloid A, and that blockade of RAGE suppressed splenic expression of proinflammatory cytokines, NF-κB activation, and accumulation of amyloid in a model of systemic amyloidosis. RAGE is a member of the immunoglobulin superfamily with a broad repertoire of ligands in addition to amyloid-associated macromolecules, including products of nonenzymatic glycoxidation (advanced glycation end products), proinflammatory mediators (S100/calgranulins), and amphoterin. In each case, the receptor recruits signal transduction mechanisms, often resulting in a sustained and pathogenic inflammatory response.
Managing acute pathology of often relies on the addressing underlying pathology and symptoms of the disease. There is currently a need in the art for new compositions to treatment of Familial amyloid polyneuropathy.